Pediatr Blood Cancer 2011;56:658–660

BRIEF REPORTHemophagocytic Lymphohistiocytosis Associated With Precursor B Acute

Lymphoblastic Leukemia

Caitlin Kelly, MD,1 Sharad Salvi, MD,1 Kenneth McClain, MD, PhD,2 and Ammar Hayani, MD1,*

We report a case of a child with precursor-B acute lymphoblas-tic leukemia (ALL) who experienced refractory thrombocytopeniaand massive splenomegaly during standard induction chemotherapy.He was diagnosed with hemophatocytic lymphohistiocytosis (HLH)during induction. Clinical and laboratory evaluation showed no evi-dence of infectious cause to HLH. Pancytopenia and HLH persisted

after consolidation therapy even with remission from leukemia. Afterfailure to control HLH with ALL-directed therapy and HLH-directedtherapy, the patient underwent unrelated donor hematopoietic stemcell transplantation 8 months after diagnosis. He is 34 months post-transplant and in remission from leukemia and HLH. Pediatr BloodCancer. 2011;56:658–660. © 2010 Wiley-Liss, Inc.

Key words: acute lymphoblastic leukemia; bone marrow transplantation; hemophagocytic lymphohistiocytosis

INTRODUCTION

Acute lymphoblastic leukemia (ALL) is the most commonmalignant neoplasm in children with a survival rate over 80% at5 years from diagnosis. In contrast, hemophagocytic lymphohistio-cytosis (HLH) is a rare disease with a median survival of less then 2months after diagnosis if untreated [1]. The criteria for a diagnosisof HLH include five of the following eight findings: (1) fever, (2)splenomegaly, (3) cytopenias affecting at least two of three lineagesin the peripheral blood, (4) hypertriglyceridemia and/or hypofibrino-genemia, (5) hemophagocytosis in bone marrow, spleen or lymphnodes, (6) low or absent NK-cell activity, (7) hyperferritinemia, and(8) high levels of sIL-2r [1]. There are two main types of HLH:familial HLH and secondary HLH. Familial forms can be asso-ciated with several identifiable gene mutations. Secondary HLHcan be induced by infection, autoimmune/inflammatory disordersand/or malignancy. We report a case of an 8-year-old male with pre-cursor B-cell ALL who had HLH during induction chemotherapy.Despite HLH-directed therapy and remission of laukemia, the HLHremained active requiring bone marrow transplantation.

CASE REPORT

An 8-year-old Caucasian male presented with a 2-monthhistory of fatigue and 1-week history of fever, emesis, diarrhea,and shoulder pain. Past medical history and family history werenegative for cancer and blood disorders. There was no consan-guinity in the family. Physical examination was notable for fever,jaundice, petechiae, ecchymosis, and massive splenomegaly. Aninitial complete blood count (CBC) revealed white blood cellcount 11,400/mcL (blasts 58%, neutrophils 4%, lymphocytes29%), hemoglobin 5.9 g/dl and platelets 3,000/mcL. Other lab-oratory testing showed lactate dehydrogenase 483 U/L (normal100–250 U/L), total bilirubin level 10 mg/dl direct bilirubin level8.1 mg/dl aspartate aminotransferase 48 U/L (normal 16–46 U/L),alanine transaminase 49 U/L (normal 10–35 U/L), and fibrinogenlevel 109 mg/dl (normal 180–400 mg/dl). PT, PTT, and D dimerwere normal. Bone marrow aspirate and biopsy showed hyper-cellularity with 90% lymphoblasts and no hemophagocytosis.Immunophenotyping of the bone marrow aspirate showed theblasts were positive for CD19, HLA-DR, and TdT, while negativefor CD20, consistent with precursor B-cell ALL. The cerebrospinal

fluid had 0 WBC per �l and negative cytology. Cytogenetictesting of the bone marrow was normal. The patient was registeredand treated on Children’s Oncology Protocol AALL0331 whichincluded induction chemotherapy of dexamethasone, vincristine,PEG-asparaginase and intrathecal cytarabine and methotrexate.

Throughout 4 weeks of induction therapy, massive splenomegalyand severe thrombocytopenia (platelet count 2,000–12,000/mcL)persisted in spite of daily platelet transfusions. The patient devel-oped severe bilateral pleural effusions. Multiple blood and urinecultures were negative for infection as well as antibodies for hepatitisA, B and C, HIV, EBV and serum PCR for CMV. Fasting triglyc-eride level was elevated at 328 mg/dl (normal <150 mg/dl). Bonemarrow aspirate on day 8 of induction showed persistent leukemia(62% blasts) and occasional hemophagocytic macrophages. Thebone marrow aspirate on day 15 of induction showed a hypocellularbone marrow with 4% blasts as well as frequent hemophagocyticmacrophages. Bone marrow aspirate on day 29 of induction revealedremission of ALL with negative minimal residual disease by flowcytometry (<0.1%), and persistent hemophagocytosis. Bilirubinlevels normalized at this time.

At the end of induction therapy, massive splenomegaly persistedwith severe thrombocytopenia ranging from 2,000 to 12,000/mcL.Due to massive splenomegaly and severe thrombocytopenia, asplenectomy was performed 2 days after completion of induc-tion. The splenic tissue pathology revealed marked congestion withextramedullary hematopoiesis and hemophagocytosis. The splenictissue showed no leukemic infiltration by routine histology orimmunophenotyping. After splenectomy was performed, there wasa transient increase in platelet count from 12,000–75,000/mcL andfewer transfusions were needed.

The patient was started on consolidation chemotherapy con-sisting of mercaptopurine, vincristine, peg-asparaginase, and

1Department of Pediatrics Advocate Hope Children’s Hospital, OakLawn, Illinois; 2Department of Pediatrics, Texas Children’s CancerCenter, Baylor College of Medicine, Houston, Texas

Conflict of interest:

*Correspondence to: Ammar Hayani, Advocate Hope Children’s Hos-pital, 4440 West 95th Street, Oak Lawn, IL 60453.E-mail: hayani@comcast.net

Received 30 December 2009; Accepted 11 May 2010

© 2010 Wiley-Liss, Inc.DOI 10.1002/pbc.22688Published online 7 December 2010 in Wiley Online Library(wileyonlinelibrary.com).

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Pediatr Blood Cancer DOI 10.1002/pbc

660 Kelly et al.

intrathecal methotrexate. After 2 months of consolidationchemotherapy, the patient continued to have severe anemia andthrombocytopenia requiring chemotherapy dose reduction and fre-quent blood transfusions. A bone marrow aspirate revealed noevidence of leukemia by histology and flow cytometry but signifi-cant hemophagocytosis. Perforin and MUNC gene analysis did notshow any mutations. NK cell function was decreased (NK 50:1 was13 (normal > 20), NK 25:1 was 7 (normal > 10) NK 12.5:1 wasnormal) and the ferritin level was elevated at 416 ng/ml (range 30–300 mg/ml). The decision was then made to modify therapy to aregime directed to treat HLH using HLH-04 protocol that includeddexamethasone, etoposide and cyclosporine [1]. Severe pancytope-nia remained after 4 months of HLH-directed chemotherapy, andbone marrow aspirate continued to show hemophagocytosis. Thepatient underwent allogeneic bone marrow transplantation 8 monthsafter his leukemia diagnosis using a conditioning regimen thatincluded cytarabine, cytoxan, and total body irradiation. His post-transplant course was complicated by mild skin graft versus hostdisease. The patient is currently in remission for both ALL and HLHand doing well 34 months after transplant with a normal CBC.

DISCUSSION

Several malignancies have been reported in association withHLH including lymphoma, leukemia, thymoma, carcinoma, multi-ple myeloma, and germ cell tumors [2]. Malignancy is hypothesizedto cause HLH due to the secretion of pro-inflammatory cytokines(e.g., TNF-alpha, IL-6) from the malignant cells, which leads toincreased activation of the macrophages [2]. Factors that may triggermalignancy-associated HLH include cancer cells, immunosuppres-sive therapy, and/or infection. In our patient there was no clinical orlaboratory evidence of infection, although the possibility of infec-tious cause cannot be completely ruled out. Our review of themedical literature revealed 24 previously reported cases of acutelymphoblastic leukemia in association with HLH, which are sum-marized in Table I. The cases were equally divided between T-celland precursor B-ALL. Infectious etiology was documented in 13cases. In patients with T cell-ALL, HLH occurred a few monthsafter the diagnosis of leukemia and all 12 patients had a fatal out-come. In contrast, HLH associated with precursor B-ALL appearsto have a better outcome with 9 of 13 patients surviving (includingthe current report). Of the four reported fatalities of precursor B-ALL-associated HLH, three had disseminated infection at the timeof death. Three patients, including ours, all with precursor B-ALL,underwent bone marrow transplant, and they all survived.

Compared to other published cases of ALL-associated HLH, ourcase is novel in that the HLH, which was diagnosed concurrent withleukemia early in the course of induction, and without documentedinfection, persisted despite remission of leukemia. In the only otherreported case of HLH during induction therapy without documentedinfection, the patient’s HLH resolved with 2 weeks of demametha-sone [3]. Our patient’s HLH, on the other hand, persisted until bonemarrow transplantation was done 8 months later.

In conclusion, diagnosis of HLH should be considered in patientswith ALL who have persistent pancytopenia and/or splenomegaly inspite of response to leukemia therapy. In such cases, HLH may notbe associated with any infection and may persist despite remissionfrom leukemia. Hemtopoietic stem cell transplantation may be aneffective option for the treatment of leukemia-associated HLH.

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Pediatr Blood Cancer DOI 10.1002/pbc